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| Human colorectal cancer cells Image Credit: National Cancer Institute |
A new study led by UCLA investigators found that combining zanzalintinib, a targeted therapy drug, and atezolizumab, an immune checkpoint inhibitor, helped patients with metastatic colorectal cancer, the second most common cause of cancer death in the U.S., live longer and control their disease better than with the standard treatment drug regorafenib.
The findings simultaneously published in The Lancet and presented at the European Society for Medical Oncology Congress; mark the first time an immunotherapy-based regimen has demonstrated a survival benefit in the vast majority of patients with metastatic colorectal cancer.
“This study represents an important step forward for a group of patients who have historically had very few treatment options,” said Dr. J. Randolph Hecht, professor of clinical medicine at the David Geffen School of Medicine at UCLA and first author of the study. “We may finally be finding ways to make immunotherapy work for more patients with colorectal cancer.”
Outcomes for metastatic colorectal cancer remain poor, with only about 15% of patients surviving five years. Patients whose cancer no longer responds to standard therapies often face limited life expectancy and few effective treatments.
While some patients with metastatic colorectal cancer benefit from immunotherapy drugs like immune checkpoint inhibitors, they only work well for the approximately 5% of patients whose tumors have specific genetic features known as MSI-H or dMMR. For the other 95% of patients, immunotherapies have not shown a clear benefit and there’s still a big need for better treatments once standard therapies stop working.
Current drugs used in later stages of treatment, including regorafenib, a targeted therapy, extend survival by an average of only about seven months. Because of this, researchers have been testing combination therapies to improve outcomes. Some combinations, like adding bevacizumab to trifluridine-tipiracil, showed modest improvements. Others, such as pairing immunotherapy with targeted drugs, have looked promising in smaller, early studies but haven’t yet shown clear survival benefits in large trials.
One possible reason immunotherapy hasn’t worked well for most colorectal cancers is that these tumors often have an immunosuppressive environment that prevents immune cells from attacking them effectively.
The new drug zanzalintinib targets several proteins, including VEGFR, MET, and TAM kinases, that help tumors grow and suppress immune responses. By blocking these, zanzalintinib may make tumors more vulnerable to immunotherapy.
Because of promising early results, researchers led by Hecht launched the international Phase 3 STELLAR-303 trial to compare zanzalintinib plus atezolizumab with regorafenib, the standard treatment, in patients with previously treated metastatic colorectal cancer.
The trial included 901 patients from 121 different sites in 16 countries with half receiving the new drug combination zanzalintinib plus atezolizumab, and half receiving the standard drug regorafenib.
After about 18 months of follow-up, patients who got the new combination lived longer than those on regorafenib with a median of 10.9 months vs. 9.4 months, meaning the combination reduced the risk of death by about 20%. About 20% of patients on the combination were still alive after two years, compared with 10% on regorafenib.
“The survival benefit was seen across all major subgroups, including patients whose cancer had spread to the liver, a group that typically doesn’t respond well to immunotherapy,” said Hecht, who is a member of the UCLA Health Jonsson Comprehensive Cancer Center and director of the UCLA Gastrointestinal Oncology Program. “We think that’s because zanzalintinib, which blocks multiple growth and immune-suppressing pathways, helps create a tumor environment that’s more receptive to immune attack.”
The combination also delayed cancer progression, meaning tumors took longer to grow or spread (median 3.7 months vs. 2.0 months), and more patients saw some tumor shrinkage (4% vs. 1% response rate).
Side effects were manageable and consistent with those expected from drugs in these classes, the researchers noted. The most common were fatigue, high blood pressure and diarrhea.
“These results show that zanzalintinib plus atezolizumab is a promising new therapy option and could redefine how we approach care for patients whose disease no longer responds to standard therapies,” Hecht said.
Published in journal: The Lancet
Authors: Prof J Randolph Hecht, MD, Young Suk Park, MD PhD, Prof Josep Tabernero, MD PhD, Prof Myung-Ah Lee, MD PhD, Prof Soohyeon Lee, MD PhD, Anna C Virgili, MD PhD, Marc Van den Eynde, MD PhD, Elisa Fontana, MD PhD, Prof Marwan Fakih, MD, Prof Gholamreza Asghari, MD FRACP, Jane So, MB ChB FRACP, Prof Alexander Stein, MD, Olivier Dubreuil, MD, Prof Lubomir Bodnar, MD PhD, Cixin Steven He, PhD, Guan Wang, MD, Robina Smith, MD, Prof Cathy Eng, MD FACP, and Prof Anwaar Saeed, MD
Source/Credit: University of California, Los Angeles / Health | Denise Heady
Reference Number: ongy102025_01